Project Summary/Abstract: This proposal describes the framework of a pathway to independence grant for Dr. Alex Yick-Lun (Steven) So. The grant will be activated immediately upon award and will provide two years of mentored support for the initial phase of the award. During these two years, Dr. So will continue his training at California Institute of Technology under the mentorship of Dr. David Baltimore. After which, this grant will provide three years of independent support for Dr. So after he obtains an assistant professorship at a new university/institute. Dr. So's research is focused on identifying and studying the role of microRNAs in the regulation of hematopoiesis and relevant diseases. Recently, Dr. So identified eight microRNAs that regulate B cell development in vitro and validated three of these (miR-125b, Let-7b, miR-27b) that control the generation of B cells in mice. Over-expression of one of these microRNAs, miR-125b, inhibited B cell development. Thus, the current proposed research will extend this work and determine the cellular and molecular mechanism by which miR-125b inhibits B cell development. Specifically, we will investigate whether miR-125b regulates B cell production through controlling the expression of Lin28 and Let-7b. Both gain-of-function and loss-of-function approaches will be applied for these studies. Interestingly, it has been shown that miR-125b regulates myeloid cell development and constitutive over-expression of miR-125b causes myeloid cancer in mice. Pertaining to human clinical relevance, miR- 125b expression has been shown to be up-regulated in certain types of human myeloid leukemia. In this proposal, Dr. So will study how miR-125b controls myelopoiesis and leukemogenesis. This will involve identifying the type of myeloid cells in which miR-125b functions to induce tumorigenesis. Next, the target genes directly repressed by miR-125b will be identified. These genes will then be investigated to determine whether they are involved in miR-125b-mediated tumorigenesis. In addition, the functional role of miR-27b in regulating B cell development will be studied. The cell types controlled by miR-27b to direct B cell production will be identified. Next, the genes regulated by miR-27b will be identified using computational and genomic strategies. The genes directly regulated by miR-27b will then be studied to determine whether they are responsible for miR-27b-mediated B cell development. Collectively, this project pertains to public health by identifying new regulators of B cell development. Also, it identifies miR-125b and potentially genes repressed by this microRNA as new targets for therapy against leukemia.